分类： 生物学 >> 生物物理学 >> 神经科学 提交时间： 2016-06-06
Yao, Minghui
Wang, Yadong
Zhang, Peng
Chen, Hong
Yuan, Zengqiang
Yao, Minghui
Xu, Zhiheng
Jiao, Jianwei
Wang, Yadong
摘要： Previous studies have shown that the Hippo pathway effector yes-associated protein (YAP) plays an important role in maintaining stem cell proliferation. However, the precise molecular mechanism of YAP in regulating murine embryonic neural stem cells (NSCs) remains largely unknown. Here, we show that bone morphogenetic protein-2 (BMP2) treatment inhibited the proliferation of mouse embryonic NSCs, that YAP was critical for mouse NSC proliferation, and that BMP2 treatment-induced inhibition of mouse NSC proliferation was abrogated by YAP knockdown, indicating that the YAP protein mediates the inhibitory effect of BMP2 signaling. Additionally, we found that BMP2 treatment reduced YAP nuclear translocation, YAP-TEAD interaction, and YAP-mediated transactivation. BMP2 treatment inhibited YAP/TEAD-mediated Cyclin D1 (ccnd1) expression, and knockdown of ccnd1 abrogated the BMP2-mediated inhibition of mouse NSC proliferation. Mechanistically, we found that Smad1/4, effectors of BMP2 signaling, competed with YAP for the interaction with TAED1 and inhibited YAP's cotranscriptional activity. Our data reveal mechanistic cross talk between BMP2 signaling and the Hippo-YAP pathway in murine NSC proliferation, which may be exploited as a therapeutic target in neurodegenerative diseases and aging.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-12
Cao, Shujuan
Yu, Liang
Ruan, Jishou
Cao, Shujuan
Yu, Liang
Ruan, Jishou
Mao, Jingyuan
Wang, Quan
Wang, Quan
Ruan, Jishou
摘要： This study begins with constructing the mini metabolic networks (MMNs) of beta amyloid (A beta) and acetylcholine (ACh) which stimulate the Alzheimer's Disease (AD). Then we generate the AD network by incorporating MMNs of A beta and ACh, and other MMNs of stimuli of AD. The panel of proteins contains 49 enzymes/receptors on the AD network which have the 3D-structure in PDB. The panel of drugs is formed by 5 AD drugs and 5 AD nutraceutical drugs, and 20 non-AD drugs. All of these complexes formed by these 30 drugs and 49 proteins are transformed into dyadic arrays. Utilizing the prior knowledge learned from the drug panel, we propose a statistical classification (dry-lab). According to the wet-lab for the complex of amiloride and insulin degrading enzyme, and the complex of amiloride and neutral endopeptidase, we are confident that this dry-lab is reliable. As the consequences of the dry-lab, we discover many interesting implications. Especially, we show that possible causes of Tacrine, donepezil, galantamine and huperzine A cannot improve the level of ACh which is against to their original design purpose but they still prevent AD to be worse as A beta deposition appeared. On the other hand, we recommend Miglitol and Atenolol as the safe and potent drugs to improve the level of ACh before A beta deposition appearing. Moreover, some nutrients such as NADH and Vitamin E should be controlled because they may harm health if being used in wrong way and wrong time. Anyway, the insights shown in this study are valuable to be developed further.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-12
Rao, Jia-Sheng
Zhao, Can
Liu, Zuxiang
Yang, Zhao-Yang
Li, Xiao-Guang
Ma, Manxiu
Liu, Zuxiang
Yang, Zhao-Yang
Li, Xiao-Guang
摘要： Purpose: To investigate the longitudinal brain regional homogeneity (ReHo) changes in nonhuman primate after spinal cord injury (SCI) by resting-state functional magnetic resonance imaging (fMRI). Methods: Three adult female rhesus monkeys underwent unilateral thoracic cord injury. A resting-state fMRI examination was performed in the healthy stage and 4, 8, and 12 weeks after the injury. The ReHo value of each voxel in the monkey brain was calculated and compared between pre- and post-SCI monkeys with paired t test. The regions of interest (ROIs) in the significantly changed ReHo regions were set. The correlations between the ReHo change and the time after injury were also determined. Results: Compared with those in healthy period, the ReHo values of the left premotor cortex and the anterior cingulate cortex (ACC) in post-SCI rhesus monkeys significantly increased in 4-week follow-up examinations. The ReHo values of posterior cingulate cortex, left precuneus, left temporal parietooccipital area, and bilateral superior parietal lobules decreased at 8-week follow-up examinations. In 12-week follow-up examinations, the ReHo values of the left postcentral gyrus, right caudate nucleus, and superior temporal gyrus increased. Correlation analysis showed positive correlations between left ACC and the postoperative time. Conclusion: SCI can change the regional synchronism of brain activity in sensorimotor system and the default mode network. These findings may help us to understand the potential pathophysiological changes in the central nervous system after SCI. (C) 2015 Elsevier Inc. All rights reserved.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-12
摘要： Normal aging is associated with greater decline in associative memory relative to item memory due to impaired recollection. Familiarity may also contribute to associative recognition when stimuli are perceived as a 'unitized' representation. Given that familiarity is relatively preserved in older adults, we explored whether age-related associative memory deficits could be attenuated when associations were unitized (i.e., compounds) compared with those non-unitized (i.e., unrelated word pairs). Young and older adults performed an associative recognition task while electroencephalogram (EEG) was recorded. Behavioral results showed that age differences were smaller for recognition of compounds than for unrelated word pairs. ERP results indicated that only compounds evoked an early frontal old/new effect in older adults. Moreover, the early frontal old/new effect was positively correlated with associative discrimination accuracy. These findings suggest that reduced age-related associative deficits under unitized condition may be associated with the presence of familiarity-based retrieval of compounds in older adults. (C) 2015 Elsevier Inc. All rights reserved.
分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间： 2016-05-11
摘要： Microcirculation dysfunction is regarded as one of important pathologies of senility, degeneration, immune disorder and many other diseases. Cerebral circulation insufficiency, energetic dysmetabolism, hypoxia-ischemia and metabolites accumulation in Alzheimer's disease (AD) have a close relation with microcirculation dysfunction. Here, we review microcirculation dysfunction playing an important role in hyperphosphorylation of Tau, A beta aggregation and cognitive impairment induced by accumulation of formaldehyde and D-ribose.
分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间： 2016-05-11
摘要： Methylation/demethylation of DNA, RNA and histone plays important roles in epigenetic functions. Formaldehyde is a significant factor participating in reversible and dynamic methylation of the biomacromolecules. As recently reported, memory formation and cognitive dysfunction are correlated with endogenous formaldehyde metabolism. Imbalance of formaldehyde metabolism affects DNA/RNA methylation and demethylation. Concentrations of endogenous formaldehyde are positively correlated with the severity of cognitive impairment of Alzheimer's patients in clinics. As an epidemiological survey shows, the levels of endogenous formaldehyde in elderly humans are negatively correlated with education years, suggesting that formaldehyde acts like a key factor in human learning and memory. "Live and learn" may mitigate the progression of age-related cognitive impairment resulted from imbalance of formaldehyde metabolism. Further investigation of endogenous formaldehyde involved in epigenetic modificaion and regulation should be carried out to understand the pathomechanism of cognition and cognitive impairment.
分类： 生物学 >> 生物物理学 >> 细胞生物学 提交时间： 2016-05-11
Zhu, Lei
Yang, Jing-Yu
Dong, Ying-Xu
Liu, Yang
Miao, Feng-Rong
Xue, Hong
Wu, Chun-Fu
Xue, Hong
Xue, Xue
Wang, Yong-Feng
摘要： In Alzheimer's disease (AD), activated microglia invade and surround beta-amyloid plaques, possibly contributing to the aggregation of amyloid beta (A beta), which affect the survival of neurons and lead to memory loss. Phosphodiesterase-5 (PDE-5) inhibitors have recently been shown a potential therapeutic effect on AD. In this study, the effects of yonkenafil (yonk), a novel PDE-5 inhibitor, on cognitive behaviors as well as the pathological features in transgenic AD mice were investigated. Seven-month-old APP/PSI transgenic mice were treated with yonk (2, 6, or 18 mg/kg, intraperitoneal injection (i.p.)) or sildenafil (slid) (6 mg/kg, i.p.) daily for 3 months and then behavioral tests were performed. The results demonstrated that yonk improved nesting-building ability, ameliorated working memory deficits in the Y-maze tasks, and significantly improved learning and memory function in the Morris water maze (MWM) tasks. In addition, yonk reduced the area of A beta plaques, and inhibited over-activation of microglia and astrocytes. Furthermore, yonk increased neurogenesis in the dentate granule brain region of APP/PSI mice, indicated by increased BrdU(+)/NeuN(+) and BrdU(+)/DCX+ cells compared to vehicle-treated transgenic mice. These results suggest that yonk could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing, inhibited the over-activation of microglia and astrocytes as well as restored neurogenesis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
分类： 生物学 >> 生物物理学 >> 肿瘤学 提交时间： 2016-05-11
Wu, Beibei
Wei, Yan
Wang, Yujing
Su, Tao
Liu, Ying
He, Rongqiao
He, Rongqiao
He, Rongqiao
Wu, Beibei
Wang, Yujing
Zhou, Lei
摘要： In addition to D-Glucose, D-Ribose is also abnormally elevated in the urine of type 2 diabetic patients, establishing a positive correlation between the concentration of uric D-Ribose and the severity of diabetes. Intraperitoneal injection of D-Ribose causes memory loss and brain inflammation in mice. To simulate a chronic progression of age-related cognitive impairment, we orally administered D-Ribose by gavage at both a low and high dose to 8 week-old male C57BL/6J mice daily for a total of 6 months, followed by behavioral, histological and biochemical analysis. We found that long-term oral administration of D-Ribose impairs spatial learning and memory, accompanied by anxiety-like behavior. Tau was hyperphosphorylated at AT8, S396, S214 and T181 in the brain. A beta-like deposition was also found in the hippocampus for the high dose group. D-Glucose-gavaged mice did not show significant memory loss and anxiety-like behavior under the same experimental conditions. These results demonstrate that a long-term oral administration of D-Ribose not only induces memory loss with anxiety-like behavior, but also elevates A beta-like deposition and Tau hyperphosphorylation, presenting D-Ribose-gavaged mouse as a model for agerelated cognitive impairment and diabetic encephalopathy.
分类： 生物学 >> 生物物理学 >> 神经科学 提交时间： 2016-05-11
Peng, Shengyi
Zhao, Siqi
Cheng, Jinbo
Huang, Li
Chen, Hong
Yuan, Zengqiang
Yan, Feng
Liu, Qingsong
Peng, Shengyi
Yuan, Zengqiang
Peng, Shengyi
摘要： All neurodegenerative diseases are associated with oxidative stress-induced neuronal death. Forkhead box O3a (FOXO3a) is a key transcription factor involved in neuronal apoptosis. However, how FOXO3a forms complexes and functions in oxidative stress processing remains largely unknown. In the present study, we show that histone deacetylase 2 (HDAC2) forms a physical complex with FOXO3a, which plays an important role in FOXO3a-dependent gene transcription and oxidative stress-induced mouse cerebellar granule neuron (CGN) apoptosis. Interestingly, we also found that HDAC2 became selectively enriched in the promoter region of the p21 gene, but not those of other target genes, and inhibited FOXO3a-mediated p21 transcription. Furthermore, we found that oxidative stress reduced the interaction between FOXO3a and HDAC2, leading to an increased histone H4K16 acetylation level in the p21 promoter region and upregulated p21 expression in a manner independent of p53 or E2F1. Phosphorylation of HDAC2 at Ser 394 is important for the HDAC2-FOXO3a interaction, and we found that cerebral ischemia/reperfusion reduced phosphorylation of HDAC2 at Ser 394 and mitigated the HDAC2-FOXO3a interaction in mouse brain tissue. Our study reveals the novel regulation of FOXO3a-mediated selective gene transcription via epigenetic modification in the process of oxidative stress-induced cell death, which could be exploited therapeutically.
分类： 生物学 >> 生物物理学 >> 神经科学 提交时间： 2016-05-05
摘要： Postoperative cognitive dysfunction (POCD) is an important complication following major surgery and general anesthesia in older patients. However, the etiology of POCD remains largely to be determined. It is unknown how surgical stress and psychological stress affect the postoperative learning and memory function in geriatric patients. We therefore established a pre-clinical model in aged C57BL/6 mice and aimed to investigate the effects of surgical stress and psychological stress on learning and memory function and the possible roles of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway. The surgical stress was induced by abdominal surgery under local anesthesia, and the psychological stress was induced by a communication box. Cognitive functions and markers of the AKT/mTOR pathway were assessed at 1, 3 and 7 days following the stress. The impairments of learning and memory function existed for up to 7 days following surgical stress and surgical stress plus psychological stress, whereas the psychological stress did not affect the cognitive function alone or combined with surgical stress. Analysis of brain tissue revealed a significant involvement of the AKT/mTOR pathway in the impairment of cognition. These data suggested that surgical stress could induce cognitive impairment in aged mice and perioperative psychological stress is not a constitutive factor of POCD. The AKT/mTOR pathway is likely involved as one of the underlying mechanisms of the development of POCD. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-05
Yuan, Qi
Chi, Shaopeng
Yang, Zhiguang
Wang, Jun
Ji, Guangju
Yuan, Qi
Deng, Ke-Yu
Xin, Hong-Bo
Sun, Le
Wang, Xiaoqun
Chi, Shaopeng
摘要： Calstabin2, also named FK506 binding protein 12.6 (FKBP12.6), is a subunit of ryanodine receptor subtype 2 (RyR2) macromolecular complex, which is an intracellular calcium channel and abundant in the brain. Previous studies identified a role of leaky neuronal RyR2 in posttraumatic stress disorder (PTSD). However, the functional role of Calstabin2 in the cognitive function remains unclear. Herein, we used a mouse model of genetic deletion of Calstabin2 to investigate the function of Calstabin2 in cognitive dysfunction. We found that Calstabin2 knockout (KO) mice showed significantly reduced performance in Morris Water Maze (MWM), long-term memory (LTM) contextual fear testing, and rotarod test when compared to wild type (WT) littermates. Indeed, genetic deletion of Calstabin2 reduced long-term potentiation (LTP) at the hippocampal CA3-CA1 connection, increased membrane excitability, and induced RyR2 leak. Finally, we demonstrated that the increase in cytoplasmic calcium activated Ca2+ dependent potassium currents and led to neuronal apoptosis in KO hippocampal neurons. Thus, these results suggest that neuronal RyR2 Ca2+ leak due to Calstabin2 deletion contributes to learning deficiency and memory impairment.
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